Adult-onset minimal change disease: the significance of histological chronic changes for clinical presentation and outcome.

INTRODUCTION: Data on pathologic features with prognostic utility in adults with minimal change disease (MCD) are limited. We assessed the relationship between histologic chronic changes and clinical presentation and outcomes. METHODS: The consecutive records of 79 patients with MCD and minimum of 6 months follow-up were retrospectively reviewed. Kidney survival was the primary endpoint (doubling serum creatinine or dialysis initiation). Secondary endpoints were time to remission and relapse. Total chronicity score was the sum of glomerulosclerosis (0-3), interstitial fibrosis (0-3), tubular atrophy (0-3), and arteriolosclerosis (0/1). RESULTS: The median renal chronicity score was 1; 77% had minimal (0-1), 18% mild (2-4), and 5% moderate (5-7) chronicity. Fifty percent had a null score; they were younger, had higher eGFR, similar proteinuria, better renal survival, and lower mortality. Mean kidney survival time was 5.7 (95% CI 5.2-6.2) years; 89% reached a form of remission at a median of 8 weeks; 31% relapsed at a mean of 26 months. Chronic changes severity predicted both relapses and kidney survival, each one-point increase in score raised with 27% the risk of relapse and with 31% the risk of dialysis initiation. Acute kidney injury (AKI) was present in 42% of the patients; they had more often mesangial proliferation, interstitial inflammation, tubular atrophy, arteriosclerosis, podocyte villous hypertrophy, and higher chronicity score. CONCLUSION: Standardized grading of chronicity was a predictor of kidney survival and disease relapse and was related to AKI. Older patients with severe nephrotic syndrome and with increased chronicity score could represent a high-risk category.

Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. METHODS: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. RESULTS: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. CONCLUSIONS: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.

RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China.

AIM: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results. METHODS: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed. RESULTS: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05). CONCLUSION: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis.

Glomerular Immune Deposits Are Predictive of Poor Long-Term Outcome in Patients with Adult Biopsy-Proven Minimal Change Disease: A Cohort Study in Korea.

BACKGROUND AND OBJECTIVES: There has been little published information on risk factors for poor long-term outcome in adult biopsy-proven minimal change disease (MCD). METHODS: Data from sixty-three adult, biopsy-proven primary MCD patients treated at a tertiary university hospital between 2003 and 2013 were analyzed. Baseline clinical and pathologic factors were assessed for the associations with composite outcome of creatinine doubling, end stage renal disease, or all-cause mortality. RESULTS: During a median (interquartile) 5.0 (2.8-5.0) years, the composite outcome occurred in 11.1% (7/63) of patients. The rate of glomerular immune deposits was 23.8% (15/63). Patients with glomerular immune deposits showed a significantly lower urine protein creatinine ratio than those without deposits (P = 0.033). The rate of non-responders was significantly higher in patients with glomerular immune deposits than in those without deposits (P = 0.033). In patients with deposits, 26.7% (4/15) developed the composite outcome, while only 6.3% (3/48) developed the composite outcome among those without deposits (P = 0.049). In multivariate Cox proportional hazards regression analysis, the presence of glomerular immune deposits was the only factor associated with development of the composite outcome (hazard ratio: 2.310, 95% confidence interval: 1.031-98.579, P = 0.047). CONCLUSION: Glomerular immune deposits were associated with increased risk of a composite outcome in adult MCD patients. The higher rate of non-responders in patients with deposits might be related to the poor outcome. Future study is needed.

Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults.

BACKGROUND: Minimal change nephropathy is a common cause of primary nephrotic syndrome in adults. However, there are few studies of its clinical course, response to treatment, and long-term outcome. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 340 consecutive adult patients with nephrotic syndrome and biopsy-proven minimal change nephropathy treated in a university hospital from 1984 until 2004. FACTORS: Treatment response groups: primary steroid resistance, frequent relapse (≥4 relapses within 1 year), infrequent relapse (≥1 relapse but not frequent relapse), and no relapse (reference group); disease pattern. OUTCOME: Medical problems after diagnosis; patient survival; renal survival. RESULTS: Median time to remission was 10 (IQR, 8-12) weeks; 179 (52.6%) had no relapse, 42 (12.4%) had infrequent relapses, 86 (25.3%) were frequent relapsers or steroid dependent, and 33 (9.7%) had primary steroid resistance. After a median follow-up of 174.7 (IQR, 119.7-235.0) months, 32 patients developed end-stage renal disease and 62 died (25 after progression to end-stage renal disease). Cox regression analysis showed that age and treatment response groups were the independent predictors of patient survival. Compared to the no-relapse group, the infrequent-relapse group had significantly better patient survival (adjusted HR, 0.19; 95% CI, 0.08-0.44; P<0.001), whereas the primary-steroid-resistance group had significantly worse patient survival (adjusted HR, 5.87; 95% CI, 1.83-18.85; P<0.001). Renal survival was excellent except in the primary-steroid-resistance group. LIMITATIONS: Retrospective study. CONCLUSIONS: A substantial proportion of adult patients with minimal change nephropathy continue to have disease flares more than 10 years after the initial presentation, and medical problems after diagnosis are common.

Clinical outcomes and predictors for ESRD and mortality in primary GN.

BACKGROUND AND OBJECTIVES: Relatively little is known about the long-term outcomes of different histologic types of primary glomerulonephritis in Asian populations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From 1993 to 2006, 987 patients undergoing renal biopsy were studied, and 580 patients (mean age=44.4 years, male=58.5%) with the four most common forms of glomerulonephritis (membranous nephropathy, focal and segmental glomerulosclerosis, IgA nephropathy, and minimal change disease) were selected for analysis. Median follow-up period was 5.9 (interquartile range=5.7) years. RESULTS: The focal and segmental glomerulosclerosis group displayed the highest incidence of ESRD (25.8%) and the fastest decline of estimated GFR (4.6 ml/min per 1.73 m(2) per year). The IgA nephropathy group also had a higher rate of ESRD than the membranous nephropathy patients (19.2% versus 4.3%, P<0.001). In contrast, the membranous nephropathy group exhibited an overall death rate similar to the focal and segmental glomerulosclerosis group (17.2% versus 14.4%) but higher than the IgA nephropathy and minimal change disease patients (4.6% and 3.7%, respectively, P<0.001). The most powerful predictor for ESRD was focal and segmental glomerulosclerosis, whereas the strongest predictor for all-cause mortality was membranous nephropathy with higher proteinuria. Protectors against ESRD included male sex and higher hemoglobin. CONCLUSIONS: Most predictors for ESRD and overall mortality found in this ethnic Chinese cohort were similar to other studies. However, some risk factors linked with distinct glomerular pathologies displayed differential clinical outcomes.

Is cyclophosphamide effective in patients with IgM-positive minimal change disease?

BACKGROUND: We analyzed the impact of immunoglobulin M (IgM) positivity on the relapse-free interval post completed course of cyclophosphamide (CYC) treatment in patients with steroid-dependent nephrotic syndrome (SDNS) and minimal change disease (MCD). METHODS: This was a retrospective chart review of all children who received CYC for SDNS and MCD between 1988 and 2009. Patients were divided into three groups based on kidney biopsy: MCD without immunoglobulin M (IgM) positivity (IgM-), MCD with IgM-positive immunofluorescence (IF) only (IgM+), and MCD with IgM-positive IF and electron-dense deposits on electron microscopy (IgM++). The relapse-free time interval to the first relapse post-CYC therapy or up to 48 months of follow-up (if no relapse occurred) was used for survival analysis. RESULTS: Forty children aged 1.5-12.3 years (15 were IgM-, 16 were IgM+, 9 were IgM++) received a cumulative CYC dose of 175 ± 30 mg/kg. The overall relapse-free survival time was 75 % at 12 months, 64 % at 24 months, 59 % at 36 months, and 56 % at 48 months, with no significant differences between the IgM groups (p = 0.80). CONCLUSIONS: Based on our results, we conclude that more than 50% of our SDNS patients with MCD remained relapse-free 4 years post-CYC treatment. No significant difference in the response to CYC was observed between patients with or without IgM positivity.

Long-term outcome of heavy proteinuria in patients under 2 years of age.

From January 1985 to July 2000, a retrospective study of 53 patients in Taiwan was performed in order to evaluate the underlying diseases causing heavy proteinuria and the clinical outcome in children under 2 years of age (33 boys and 20 girls). Renal biopsy or autopsy was performed in 26 of the children. Renal pathology revealed 2 patients with congenital nephrosis (CNS) (7.7%), 4 with diffuse mesangial sclerosis (DMS) (15.4%), 4 with minimal change nephrotic syndrome (MCNS) (15.4%), 5 with focal segmental glomerulosclerosis (FSGS) (19.2%), 9 with IgM nephropathy in (34.6%), and 2 with hepatitis B virus-associated membranous glomerulonephritis (7.7%). Based on available histology and family history of heavy proteinuria progressing to end-stage renal disease (ESRD), patients were divided into two groups. Group I comprised 10 patients, including CNS (2 cases), DMS (4 cases), and 4 children with a familial history of heavy proteinuria progressing to ESRD. All patients in group I were initially steroid resistant. After methylprednisolone pulse therapy plus cyclosporin A treatment, no patients with CNS or DMS responded, but the other 4 patients experienced a remission. Group II comprised 43 patients; 19 patients (44.2%) were initially steroid resistant. Of these steroid-resistant patients, all experienced remission after methylprednisolone pulse therapy plus cyclosporin A, except 3 children with FSGS. One experienced a thromboembolic event during his clinical course. In conclusion, steroid-resistant nephrotic syndrome (NS) was more common than steroid-sensitive NS in Chinese patients under 2 years of age. Patients with CNS, DMS, or a family history of heavy proteinuria progressing to ESRD had a poor prognosis. Methylprednisolone pulse therapy plus cyclosporin A treatment achieved remission in some children who were initially steroid resistant. This study indicates that children with conditions associated with poor steroid responsiveness (e.g., CNS, DMS) do not respond to immunosuppressive therapy, but other children under 2 years of age, including those with a family history of progression to ESRD, may benefit from aggressive immunosuppressive therapy.

Minimal change nephrotic syndrome in children: deaths during the first 5 to 15 years' observation. Report of the International Study of Kidney Disease in Children.

Of 521 children with a previously untreated nephrotic syndrome, as defined by proteinuria greater than or equal to 40 mg/h/m2 and serum albumin less than or equal to 2.5 g/dL, entering the International Study of Kidney Disease in Children between January 1967 and April 1976, 389 showed minimal changes on renal biopsy. Of these, seven boys and three girls died, all before July 1972. Infection was the cause of death in six patients. One child died of dural sinus thrombosis, one died as a result of cardiorespiratory failure following salt-poor albumin infusion, and another died from chronic renal failure due to focal and segmental glomerulosclerosis not apparent on initial biopsy. The mode of death in the remaining child was uncertain. Analysis according to histopathologic subgroups of minimal change disease showed no statistically significant differences in the incidence of deaths, although mesangial abnormalities and tubular atrophy were associated with higher mortality than nil disease or focal glomerular obsolescence. Nine of the ten children who died had either failed to respond to initial prednisone therapy (initial nonresponders, n = 5), or responded but relapsed during the initial 8 weeks of treatment (early relapser, n = 4), even though only one quarter of the total sample were nonresponders or early relapsers (P less than .0005). Nearly one fifth of all initial nonresponders with minimal change nephrotic syndrome died. Thus the pattern of response to initial steroid therapy in patients with minimal change nephrotic syndrome may have prognostic significance.